Bacterial vaginosis is the most common form of infectious vaginitis, accounting for 45% of symptomatic cases and estimated to be present in 15% of asymptomatic sexually active women. See Breen, J., ed., The Gynecologist and the Older Patient, pp. 304-305 (1988). Bacterial vaginosis (also called nonspecific vaginitis) is a polymicrobial vaginal infection believed to be caused by an increase in the number of anaerobic organisms with a concomitant decrease in lactobacilli in the vagina. The decrease in the number of lactobacilli in the vagina has a dual effect, i.e., (i) a decreased competition for nutrients and (ii) a decrease in the amount of lactic acid present, thus allowing for the multiplication of opportunistic pathogens in the vagina, whose growth is normally suppressed by the lactobacilli. The principal pathogens associated with bacterial vaginosis are believed to be Gardnerella vaginalis and anaerobes of the Mobiluncus species. However, numerous other pathogenic anaerobes are also believed to be involved in the etiology of vaginosis. See Kaufman et al., Benign Diseases of the Vulva and Vagina, 3rd ed., pp. 401-418 (1989). Thus, bacterial vaginosis is considered a broad spectrum infection requiring a broad spectrum treatment.
Clinically, bacterial vaginosis presents itself as a superficial vaginal infection with few irrative symptoms and no inflammatory response. Some noticeable symptoms include an unpleasant smell, an elevated vaginal pH greater than about 5.0, a thin homogeneous discharge, the presence of Gardnerella clue cells and a high succinate/lactate ratio (.gtoreq.0.4). See, e.g., Livengood et al., "Bacterial Vaginosis: Diagnostic and Pathogenic findings during Topical Clindamycin Therapy," Am. J. Obstet. Gynecol., vol. 163, No. 2, p. 515 (August 1990).
It is believed that the composition of organic acids in the vagina shifts from primarily lactic acid (pK.sub.a =3.86) to succinic acid (pK.sub.a1 =4.21, pK.sub.a2 =5.64) as a result of the decrease in the lactobacilli, which produce lactic acid, and a rise in Mobiluncus, which produce succinic acid. This shift in acid composition tends to raise the pH of the vagina. It is unclear whether the change in acidity is a cause or effect of the infection. However, it is known that certain anaerobes will grow better at a higher pH than is normally present in the vagina. It is thus believed that lowering the vaginal pH is an effective measure against the infection.
Moreover, the odor of the amines which are produced in the vagina is known to increase at higher pH's because unprotonated, volatile, amines are present in basic conditions. Additionally, the high pH level is thought to allow the anaerobes to grow and produce the amines that are present in a bacterial vaginosis infection.
Generally, current treatment regimens for bacterial infection of the vagina, including vaginosis, involve the use of various broad spectrum antibiotics, most particularly metronidazole, administered either topically or orally. Antibiotics are undesirable, however, because they may kill a broad range of the normal bacterial flora in the vagina, including the beneficial lactobacilli. This may cause secondary complications, since the lactobacilli keep various opportunistic pathogens in the vagina, such as the yeasts Candida albicans and Torulopsis glabrata and some anaerobes, including, perhaps, the Mobiluncus in check.
The treatment might then necessitate a further treatment regimen, such as the ingestion of cultured dairy products to replace the lactobacilli in the body, as well as treatment by antifungal agents. Moreover, a rise in the level of anaerobes due to a lack of lactobacilli could further complicate the current infection.
Additionally, if antibiotics are taken orally, other beneficial bacteria in the body, e.g., the E. coli in the gastrointestinal tract, may be killed. This can result in gastrointestinal upset (e.g., diahorrea), a common side effect of metronidazole, and further discomforts, if not worse.
Moreover, the use of antibiotics to treat relatively benign infections, such as vaginosis, particularly when systemically administered, is disfavored since such treatment can cause other, more pathogenic bacteria to develop resistance to the antibiotic, which would then not be effective when an antibiotic is really needed to treat a serious bacterial infection in a patient.
Douches comprising hydrogen peroxide have shown some effectiveness as treatments against bacterial vaginosis. See, Kaufman, at 415. However, vinegar douches have been used without much success.
Topically administered creams comprising sulfa drugs also have been used as a means of treating bacterial vaginosis. The acidity of the drugs is thought to provide their limited effectiveness in treating vaginosis. See, e.g., Older Patient at 305. Moreover, the relative toxicity of sulfa drugs render them undesirable for treatment of such non-life threatening, although unpleasant, bacterial diseases. Topically administered nonoxynol-9, a spermicide, has also shown limited efficacy in preventing the transmission of bacterial vaginosis. See Barbone et al., "A Follow-up Study of Methods of Contraception, Sexual Activity and Rates of Trichomoniasis, Candidiasis and Bacterial Vaginosis," Am. J. Obstet. Gynecol., Vol. 163, No. 2, p. 510 (August 1990).
In one study, women with bacterial vaginosis were treated topically with an acidic gel. Andersch et al. "Treatment of Bacterial Vaginosis with an Acid Cream: A Comparison between the Effect of Lactate-Gel and Metronidazole", Gynecol Obstet Invest 21:19-25 (1986). Following a diagnosis of bacterial vaginosis, as determined by odor, pH and cell cultures, women in the study were treated with either a daily topical treatment of a lactate-gel, buffered to a pH of 3.5, or with 500 mg metronidazole, given orally twice a day (500.times.2).
The efficacy against bacterial vaginosis of both treatment regimens were compared and found to be similar. However, it was found that the gel had an effect only on the number of anaerobes and not the Gardneralla nor the helpful lactobacilli. Moreover, none of the side effects, such as the nausea reported in 30% of those women taking metronidazole, occurred in women using the gel.
While the above described study indicates that agents that cause a reduction in vaginal pH can be beneficial in the treatment of vaginosis, the problem with such aforementioned topical applications and douches is that the vagina has a clearance time of 30-90 minutes, so that all the contents of the vagina will be expelled therefrom within that time period. Thus, topical treatments and douche ingredients will be expelled from the vagina quickly, leaving the vagina vulnerable to a resurgence of infectious growth. A topical application that would remain in place for greater than 90 minutes would be of great benefit.
In addition, the assignees of the present invention commissioned a study wherein the vaginal pH of postmenopausal women was lowered over an extended period of time by application of REPLENS.RTM., a product made and used according to a parent application of the present application, U.S. application Ser. No. 07/732,738, which contains a cross-linked polycarboxylic acid, polycarbophil, as compared to the application of KY JELLY.RTM.. See Zinny, M. and Lee, S., "Double-Blind Study of the Comparative Effects of Two Gels on Vaginal pH in Postmenopausal Women", Today's Therapeutic Trends 8(4): 65-72, 1991. However, this study dealt with postmenopausal women, in whom, due to estrogren deficiency, there is a low level of glycogen, and thereby a low level of lactobacilli and a relatively high vaginal pH. (See Kaufman, p. 420). The different vaginal flora present in postmenopausal women often presents different difficulties in treating vaginal conditions in post-menopausal women than in pre-menopausal women.
Agents that would remain in the vagina for more than 90 minutes include bioadhesives, e.g., such as those cross-linked polycarboxylic acid polymers disclosed as carriers for treating agents in U.S. Pat. No. 4,615,697. While the use of such bioadhesives is known in the art to deliver drugs, they were not known as pH buffers. The bioadhesive effect of the polymers is useful in the present application of these polymers to keep the polymers in place on the vaginal lining. This results in an extended maintenance of an acidic pH in the vagina which ultimately can result in a reduction in the numbers of the microbes involved in the causation of vaginosis. The bioadhesive properties of the polymer prevent it from being rapidly cleared from the vagina as occurs with other topically applied agents. Thus, the present invention provides a novel use of these bioadhesive polymers to maintain the pH of the vagina for long periods of time which reduces the numbers of harmful microorganisms that cause vaginosis and prevents the unpleasant odor attendant to vaginosis without resorting to antibiotics.